title: Structure-based design of small-molecule ligands of phosphofructokinase-2 activating or inhibiting glycolysis.
abstract: Glycolysis lies at the basis of metabolism and cell energy supply. The disregulation of glycolysis is involved in such pathological processes as cancer proliferation, neurodegenerative diseases, and amplification of ischemic damage. Phosphofructokinase-2 (PFK-2), a bifunctional enzyme and regulator of glycolytic flux, has recently emerged as a promising anticancer target. Herein, the computer-aided design of a new class of aminofurazan-triazole regulators of PFK-2 is described along with the results of their in vitro evaluation. The aminofurazan-triazoles differ from other recently described inhibitors of PFK-2 and demonstrate the ability to modulate glycolytic flux in rat muscle lysate, producing a twofold decrease by inhibitors and fourfold increase by activators. The most potent compounds in the series were shown to inhibit the kinase activity of the hypoxia-inducible form of PFK-2, PFKFB3, as well as proliferation of HeLa, lung adenocarcinoma, colon adenocarcinoma, and breast cancer cells at concentrations in the low micromolar range.
authors.affiliation: Quantum Pharmaceuticals LLC, Kosmonavta Volkova 6A, 1205, Moscow 125171, Russia. tim.pyrkov@q-pharm.com
authors.forename: Timothy V
authors.initials: TV
authors.lastname: Pyrkov
authors.forename: Irina A
authors.initials: IA
authors.lastname: Sevostyanova
authors.forename: Elena V
authors.initials: EV
authors.lastname: Schmalhausen
authors.forename: Andrei N
authors.initials: AN
authors.lastname: Shkoporov
authors.forename: Andrei A
authors.initials: AA
authors.lastname: Vinnik
authors.forename: Vladimir I
authors.initials: VI
authors.lastname: Muronetz
authors.forename: Fedor F
authors.initials: FF
authors.lastname: Severin
authors.forename: Peter O
authors.initials: PO
authors.lastname: Fedichev
mesh_terms: D000818:Animals; D001665:Binding Sites; D020134:Catalytic Domain; D049109:Cell Proliferation / Q000187:drug effects; D017076:Computer-Aided Design; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006019:Glycolysis / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D051379:Mice; D062105:Molecular Docking Simulation; D018482:Muscle, Skeletal / Q000378:metabolism; D025481:Phosphofructokinase-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D054852:Small Molecule Libraries; D014230:Triazoles; D025481:Phosphofructokinase-2
keywords: cancer; drug design; glycolysis; metabolism; phosphofructokinases